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Article

PubMed

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Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma

International journal of cancer. 2019 Aug 01 ; 145 (3) : 686-693. [epub] 20190207

Int J Cancer
ISSN 1097-0215 | 0020-7136
Source

Language English Country United States Media print-electronic

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link https://www.medvik.cz/link/pmid30672594

PubMed 30672594
DOI 10.1002/ijc.32127
Knihovny.cz E-resources

Keywords
I157T, K3326X, PANDoRA consortium, pancreatic cancer, rs11571833, rs17879961,
MeSH
Checkpoint Kinase 2 genetics MeSH
Carcinoma, Pancreatic Ductal genetics MeSH
Genetic Predisposition to Disease MeSH
Genes, BRCA2 * MeSH
Polymorphism, Single Nucleotide MeSH
Middle Aged MeSH
Humans MeSH
Pancreatic Neoplasms genetics MeSH
BRCA2 Protein genetics MeSH
Aged MeSH
Case-Control Studies MeSH
Germ-Line Mutation MeSH
Check Tag
Middle Aged MeSH
Humans MeSH
Male MeSH
Aged MeSH
Female MeSH
Publication type
Journal Article MeSH
Research Support, Non-U.S. Gov't MeSH
Names of Substances
BRCA2 protein, human MeSH Browser
Checkpoint Kinase 2 MeSH
CHEK2 protein, human MeSH Browser
BRCA2 Protein MeSH

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10-3 and ORdom = 1.74, 95% CI = 1.15-2.63, p = 8.57 × 10-3 , respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.

1st Propaedeutic Surgical Department Hippocratio General Hospital Athens Medical School National and Kapodistrian University of Athens Athens Greece

ARC Net Applied Research on Cancer Centre University of Verona Verona Italy

Department of Basic Medical Sciences Laboratory of Biology Medical School National and Kapodistrian University of Athens Athens Greece

Department of Clinical Biochemistry Herlev and Gentofte Hospital Copenhagen University Hospital Copenhagen Denmark

Department of Digestive Tract Diseases Medical University of Lodz Lodz Poland

Department of Gastroenterology Lithuanian University of Health Sciences Kaunas Lithuania

Department of General Visceral and Thoracic Surgery University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Hematology Medical University of Lodz Lodz Poland

Department of Laboratory Medicine University Hospital of Padova Padova Italy

Department of Massa Carrara Oncological Azienda USL Toscana Nord Ovest Carrara Italy

Department of Oncology Faculty of Medicine and Dentistry Palacky University Olomouc and University Hospital Olomouc Olomouc Czech Republic

Department of Oncology Herlev and Gentofte Hospital Copenhagen University Hospital Copenhagen Denmark